KR102695633B1 - Tetrahydroisoquinoline-containing pyrimidine derivatives and their uses in tubercular therapy - Google Patents

Abstract

The present invention relates to a tetrahydroisoquinoline derivative containing pyrimidine, an isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same as an active ingredient for preventing or treating tuberculosis. The tetrahydroisoquinoline derivative containing pyrimidine of the present invention, an isomer thereof or a pharmaceutically acceptable salt thereof exhibits an excellent inhibitory effect against active and inactive tuberculosis bacilli, and therefore can be usefully used in the treatment of tuberculosis.

Description

Tetrahydroisoquinoline-containing pyrimidine derivatives and their uses in tubercular therapy

The present invention relates to the prevention and treatment of tuberculosis disease, comprising a tetrahydroisoquinoline derivative including a novel pyrimidine as an effective ingredient.

Tuberculosis (TB) is a respiratory infection caused by the tubercle bacilli (Mycobacterium tuberculosis). It is a disease that has been around for as long as human history and is one of the oldest diseases that has not been conquered to this day.

According to the World Health Organization (WHO) in 2018, it is known as the most dangerous infectious disease along with AIDS, causing 1.6 million deaths worldwide. The number of patients has been decreasing since 2011, but it is reported that the number of patients will increase somewhat after COVID-19.

Not only is there a lack of development of new anti-tuberculosis drugs, but treatment is becoming increasingly difficult due to resistance to existing drugs that have been used for the past 20 years. Recently, multi-drug resistant tuberculosis groups that are resistant to basic anti-tuberculosis drugs such as Rifampin (RMP) and Isoniazid (INH) and super tuberculosis groups that are resistant not only to Rifampin (RMP) and Isoniazid (INH), but also to one of the three injectable drugs (Capreomycin, Kanamycin, Amikacin) and one of the fluoroquinolones have emerged, necessitating the development of new anti-tuberculosis drugs with new mechanisms of action.

Mycobacterium tuberculosis Decaprenylphosphoryl-β-D-ribose Oxidase Inhibitors: Expeditious Reconstruction of Suboptimal Hits into a Series with Potent in Vivo Activity, J. Med. Chem. 2020, 63, 2557-2576.

The present invention aims to provide a tetrahydroisoquinoline derivative and a salt thereof containing a pyrimidine having excellent activity against mycobacteria as a potential new anti-tuberculosis drug.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating tuberculosis disease, which contains as an effective ingredient at least one selected from a tetrahydroisoquinoline derivative containing pyrimidine and a salt thereof.

To solve the above problem, the present invention provides a tetrahydroisoquinoline derivative and a salt thereof containing a pyrimidine represented by the following chemical formula 1, which has an excellent effect on the treatment of tuberculosis, particularly on the inhibition of the activity of mycobacteria.

[Chemical Formula 1]

In the above chemical formula 1,

R ₁ and R ₂ are independently hydrogen, halogen, nitro, amino, (C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkyloxy, (C ₂ -C ₇ )alkenyl, (C ₆ -C ₁₂ )aryl, (C ₃ -C ₁₂ )heterocycloalkyl or (C ₂ -C ₁₂ )heteroaryl, except when both R ₁ and R ₂ are hydrogen,

The aryl, heterocycloalkyl or heteroaryl of the above R ₁ and R ₂ is selected from the group consisting of halogen, nitro, amino, hydroxy, aldehyde, carboxylic acid, ketone, (C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkoxy, hydroxy(C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkylaminoketone, or is further substituted with one or more substituents selected from di(C ₁ -C ₇ )alkylaminoketone,

The above (C ₃ -C ₁₂ )heterocycloalkyl or (C ₂ -C ₁₂ )heteroaryl contains 1 to 4 heteroatoms selected from N, O, S,

R ₃ is independently substituted with a substituent selected from hydrogen, (C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkoxyketone or di(C ₁ -C ₇ )alkylaminoketone,

R ₄ is independently substituted with hydrogen or (C ₁ -C ₇ )alkyl,

R ₅ is independently substituted with one or more substituents selected from hydrogen, halogen, amino, nitro, (C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkyloxy, halo(C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkylketoamino, phenylketoamino or phenylurea,

Ak is (C ₁ -C ₇ )alkyl;

m is an integer from 0 to 4,

n is an integer from 0 to 2.

In addition, the present invention provides a tetrahydroisoquinoline derivative, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R ₁ in the chemical formula 1 is substituted with (C ₃ -C ₁₂ )heterocycloalkyl or (C ₂ -C ₁₂ )heteroaryl.

The heterocycloalkyl or heteroaryl of the above R ₁ and R ₂ is selected from the group consisting of halogen, nitro, amino, hydroxy, aldehyde, carboxylic acid, ketone, (C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkoxy, hydroxy(C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkylaminoketone, or further substituted with one or more substituents selected from di(C ₁ -C ₇ )alkylaminoketone.

In addition, the present invention provides a tetrahydroisoquinoline derivative comprising a pyrimidine of the following chemical formula 2, wherein R ₁ in the chemical formula 1 is substituted with morpholine, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical formula 2]

R ₂ , R ₃ , R ₄ , R ₅ , m and n in the above chemical formula 2 are the same as in chemical formula 1.

In addition, the present invention provides a tetrahydroisoquinoline derivative comprising a pyrimidine of the following chemical formula 3, wherein R ₁ in the chemical formula 1 is substituted with pyrrole, an isomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 3]

In the above chemical formula 3,

R ₆ is independently hydrogen, halogen, nitro, amino, aldehyde, carboxylic acid, (C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkoxy, hydroxy(C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkylaminoketone, Or substituted with a substituent selected from di(C ₁ -C ₇ )alkylaminoketone,

Ak is (C ₁ -C ₇ )alkyl;

n is an integer from 0 to 2;

R ₂ , R ₃ , R ₄ , R ₅ and m in the above chemical formula 2 are the same as in chemical formula 1.

In addition, the present invention provides a pharmaceutical composition for the prevention and treatment of tuberculosis disease, containing at least one effective ingredient selected from a tetrahydroisoquinoline derivative including a pyrimidine of the present invention and a salt thereof.

Preferably, a pharmaceutical composition for preventing or treating tuberculosis according to one embodiment of the present invention may contain 0.001 to 1 wt% of at least one effective ingredient selected from tetrahydroisoquinoline derivatives containing pyrimidine and salts thereof.

Preferably, the pharmaceutical composition for preventing or treating tuberculosis disease according to one embodiment of the present invention may additionally contain a pharmaceutically acceptable carrier, diluent or excipient.

The "pharmaceutically acceptable salt" of the compound of the above chemical formula 1, 2 or 3 can be prepared by a method conventional in the art, and includes, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, and carbonic acid; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin); salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, and proline; salts with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid; It includes salts with sulfonic acids such as toluenesulfonic acid, metal salts resulting from reaction with alkali metals such as sodium and potassium, or salts with ammonium ions.

The term “halogen” used in the present invention means fluoro, bromo, chloro or iodo, and preferably bromo or iodo.

The term "alkyl" as used in the present invention means a linear or branched saturated C ₁ to C ₇ , preferably C ₁ to C ₅ , more preferably C ₁ to C ₃ hydrocarbon radical chain. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and hexyl.

The term "alkoxy" as used in the present invention means a -ORa group, where Ra is alkyl as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and the like.

The term “aryl” used in the present invention refers to an organic radical derived from an aromatic hydrocarbon by the removal of one hydrogen, and includes a single or fused ring system, suitably containing 4 to 7, preferably 5 or 6 ring atoms in each ring, and even includes a form in which multiple aryls are connected by single bonds. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, and the like.

The “heteroaryl” described in the present invention refers to an aryl group containing 1 to 4 heteroatoms selected from B, N, O, S, SO ₂ , P(=O), Si and P as aromatic ring skeletal atoms, and the remaining aromatic ring skeletal atoms are carbon, and is a 5-6 membered monocyclic heteroaryl, and a polycyclic heteroaryl condensed with one or more benzene rings, and may be partially saturated. In addition, the heteroaryl in the present invention also includes a form in which one or more heteroaryls are linked by a single bond.

The “heterocycloalkyl” described in the present invention contains 1 to 4 heteroatoms selected from B, N, O, S, SO ₂ , P(=O), Si and P as ring skeletal atoms, and may be a 5 to 6-membered monocyclic heterocycle, and a polycyclic heterocycle fused with one or more rings.

Hereinafter, a method for producing a tetrahydroisoquinoline derivative containing a pyrimidine represented by the chemical formula 1 of the present invention is described in detail.

According to a preferred embodiment of the present invention, a tetrahydroisoquinoline derivative comprising a pyrimidine of the chemical formula 1 of the present invention can be prepared according to a synthetic route represented by the following reaction scheme 1.

[Reaction Formula 1]

As shown in the above reaction scheme 1, the compounds of the present invention were prepared by using 4,6-dichloropyrimidine as a starting material and containing a pyrimidine having a morpholine group (chemical formula 2) and a pyrrole group (chemical formula 3) introduced as a tetrahydroisoquinoline derivative.

A pharmaceutical composition comprising at least one effective ingredient selected from the tetrahydroisoquinoline derivatives including pyrimidine of the present invention, isomers thereof, and pharmaceutically acceptable salts thereof can be administered orally or parenterally during clinical administration and can be used in the form of general pharmaceutical preparations. When formulated, it can be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are generally used.

Solid preparations for oral administration can be prepared by mixing at least one excipient, such as starch, calcium carbonate, sucrose, lactose or gelatin, with a tetrahydroisoquinoline derivative containing one or more pyrimidines according to the present invention, an isomer thereof or a pharmaceutically acceptable salt thereof. In addition, lubricants such as magnesium stearate or talc can also be used in addition to simple excipients.

Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups, and in addition to the commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents or preservatives can be used.

Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations or suppositories. The non-aqueous solutions or suspensions may include vegetable oils such as propylene glycol, polyethylene glycol or olive oil, injectable esters such as ethyl oleate, and the suppository base may include withepsol, macrogol, Tween 61, cacao butter, laurin butter, glycerol or gelatin.

In addition, the pharmaceutical composition for preventing or treating tuberculosis according to the present invention may contain at least one selected from the tetrahydroisoquinoline derivatives including the pyrimidine of the present invention, isomers thereof, and pharmaceutically acceptable salts thereof as an active ingredient in an amount of 0.001 to 1 wt%.

The human dosage of the pharmaceutical composition for preventing or treating tuberculosis of the present invention may vary depending on the patient's age, body weight, sex, dosage form, health condition, and disease severity, and is generally 0.1 to 1000 mg/day, preferably 1 to 500 mg/day, based on an adult patient weighing 70 kg, and may be administered once or several times a day in divided doses at regular intervals.

The tetrahydroisoquinoline derivatives and salts thereof containing pyrimidine of the present invention exhibit excellent inhibitory effects against active and inactive tuberculosis bacteria, especially mycobacteria, and therefore can be very usefully used in the treatment and prevention of tuberculosis.

The pharmaceutical composition for preventing and treating tuberculosis of the present invention can be usefully used for the treatment and prevention of tuberculosis by containing at least one selected from the tetrahydroisoquinoline derivative containing pyrimidine of the present invention and its salt as an effective ingredient.

Figure 1 shows an example of measuring the activity of Isoniazid against one drug-resistant strain.

The present invention will be described in more detail through the following examples. These examples are only intended to explain the present invention more specifically, and it will be obvious to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention.

Example 1. Preparation of 4-(6-Chloropyrimidin-4-yl)morpholine

4,6-dichloropyrimidine (5.0 g, 33.56 mmol) and morpholine (6.08 g, 70.48 mmol) were dissolved in isopropyl alcohol (100 mL) and stirred under reflux at 110°C for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water (200 mL) was added, and extracted twice with ethyl acetate (200 mL). The organic extract was washed with brine (100 mL). The washed organic extract was dried over magnesium sulfate (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to obtain 6.5 g (97%) of the title compound as a white solid.

^1H NMR (300 MHz, CDCl ₃ ) δ ppm 8.39 (s, 1H), 6.49 (s, 1H), 3.78 (dd, J = 5.8, 4.0 Hz, 4H), 3.63 (t, J = 4.9 Hz, 4H) ).

Example 2. Preparation of 1-(6-Morpholinopyrimidin-4-yl)piperidine-4-carboxylic acid

4-(6-chloropyrimidin-4-yl)morpholine (6.0 g, 30.1 mmol), piperidine-4-carboxylic acid (11.66 g, 90.3 mmol), K ₂ CO ₃ (20.8 g, 150.5 mmol) obtained in the above Example 1 were dissolved in dimethylformamide (90 mL) and stirred at 110°C for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water (100 mL) was added, and the mixture was acidified (pH 4) with 1 N HCl. The acidified mixture was concentrated under reduced pressure, dissolved in a 1:1 solution of dichloromethane: chloroform, and the resulting solid was filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (5% MC) to obtain 4.12 g (47%) of the title compound of the above chemical formula as a white solid.

^1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.07 (s, 1H), 5.90 (s, 1H), 4.24 (dt, J = 13.6, 4.0 Hz, 2H), 3.63 (t, J = 4.8 Hz) , 4H), 3.48 (t, J = 4.8 Hz, 4H), 2.93 (ddd, J = 13.8, 11.4, 2.8 Hz, 2H), 1.82 (dd, J = 13.5, 3.8 Hz, 2H), 1.55 - 1.38 ( m, 2H).

Example 3. Preparation of (3,4-Dihydroisoquinolin-2(1H)-yl)(1-(6-morpholinopyrimidin-4-yl)- piperidin-4-yl)methanone

1-(6-morpholinopyrimidin-4-yl) piperidine-4-carboxylic acid (50 mg, 0.18 mmol), 1,2,3,4-tetrahydro-isoquinoline (30 mg, 0.22 mmol), HBTU (103 mg, 0.27 mmol) and triethylamine (Et ₃ N, 40 mg, 0.36 mmol) obtained in the above Example 2 were dissolved in dichloromethane (3 mL) and stirred at room temperature for 12 hours. After completion of the reaction, water (10 mL) was added to the mixture and extracted twice using dichloromethane (10 mL). The organic extract was dried over magnesium sulfate (MgSO ₄ ) and filtered. The filtrate was concentrated under reduced pressure and 81 mg (50%) of the title compound of the above chemical formula was obtained in the form of a solid using column chromatography (EA:Hex = 1:3). (Compound 1)

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.27 (s, 1H), 7.24 - 7.17 (m, 4H), 5.62 (s, 1H), 4.74 (d, J = 9.1 Hz, 2H), 4.41 - 4.34 (m, 2H), 3.82 - 3.77 (m, 6H), 3.56 (t, J = 4.8 Hz, 4H), 3.06 - 3.00 (m, 2H), 2.87 (d, J = 6.4 Hz, 2H), 2.82 ( s, 1H), 1.87 - 1.82 (m, 4H).

Example 4. (5,7-Dichloro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)(1-(6-morpholinopyrimidin-4-yl)piperidin-4-yl)methanone (compound 2)

The same procedure as in Example 3 was followed except that 5,7-Dichloro-1,2,3,4-tetrahydroisoquinoline was used to obtain the following structural compound. (Compound 2)

^1H NMR (300 MHz, CDCl ₃ ) δ ppm 8.26 (s, 1H), 7.31 (s, 1H), 7.10 (s, 1H), 5.62 (s, 1H), 4.71 (d, J = 15.1 Hz, 2H ), 4.39 (d, J = 13.2 Hz, 2H), 3.80 (t, J = 4.8 Hz, 6H), 3.56 (t, J = 4.9 Hz, 4H), 3.05 - 2.93 (m, 3H), 2.85 (s) , 2H), 1.82 (d, J = 12.7 Hz, 4H).

Example 5. (6-Fluoro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)(1-(6-morpholinopyrimidin-4-yl)piperidin-4-yl)methanone (compound 3)

The same procedure as in Example 3 was followed except that 6-Fluoro-1,2,3,4-tetrahydroisoquinoline was used, thereby obtaining the following structural compound. (Compound 3)

^1H NMR (300 MHz, CDCl ₃ ) δ ppm 8.26 (s, 1H), 7.12 (d, J = 6.3 Hz, 1H), 6.92 (q, J = 9.3 Hz, 2H), 5.62 (s, 1H), 4.70 (d, J = 7.5 Hz, 2H), 4.38 (d, J = 13.1 Hz, 2H), 3.80 (t, J = 5.0 Hz, 6H), 3.56 (t, J = 4.8 Hz, 4H), 2.99 ( q, J = 8.8, 5.9 Hz, 3H), 2.87 (d, J = 7.8 Hz, 2H), 1.82 (d, J = 12.8 Hz, 4H).

Example 6. (1-(6-Morpholinopyrimidin-4-yl)piperidin-4-yl)(5-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 4)

The same procedure as Example 3 was followed, except that 5-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 4)

^1H NMR (300 MHz, CDCl ₃ ) δ ppm 8.27 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.38 - 7.33 (m, 2H), 5.63 (s, 1H), 4.80 (s , 2H), 4.41 (d, J = 13.0 Hz, 2H), 3.80 (t, J = 4.9 Hz, 6H), 3.56 (t, J = 4.9 Hz, 4H), 3.14 (d, J = 5.8 Hz, 1H) ), 3.00 (t, J = 12.4 Hz, 3H), 2.87 (dt, J = 10.0, 5.0 Hz, 1H), 1.85 (d, J = 7.4 Hz, 4H).

Example 7. (5-Fluoro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)(1-(6-morpholinopyrimidin-4-yl)piperidin-4-yl)methanone (compound 5)

The same procedure as in Example 3 was followed except that 5-Fluoro-1,2,3,4-tetrahydroisoquinoline was used, thereby obtaining the following structural compound. (Compound 5)

^1H NMR (300 MHz, CDCl ₃ ) δ ppm 8.26 (s, 1H), 7.20 (d, J = 7.3 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 5.62 (s, 1H), 4.75 (d, J = 13.0 Hz, 2H), 4.39 (d, J = 12.5 Hz, 2H), 3.80 (t, J = 4.9 Hz, 6H), 3.56 (t, J = 4.8 Hz, 4H), 3.06 - 2.93 (m, 3H), 2.86 (d, J = 6.5 Hz, 2H), 1.85 (s, 4H).

Example 8. (5,8-Dibromo-6,7-dichloro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)(1-(6-morpholinopyrimidin-4-yl)piperidin-4-yl)methanone (compound 6)

The same procedure as in Example 3 was followed, except that 5,8-Dibromo-6,7-dichloro-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 6)

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.26 (s, 1H), 5.62 (s, 1H), 4.76 - 4.66 (m, 2H), 4.39 (s, 2H), 3.80 (t, J = 4.8 Hz , 6H), 3.56 (t, J = 4.9 Hz, 4H), 2.98 (d, J = 13.1 Hz, 3H), 2.88 (dd, J = 10.2, 5.0 Hz, 2H), 1.84 (s, 4H).

Example 9. (5,7-Dichloro-6-nitro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)(1-(6-morpholinopyrimidin-4-yl)piperidin-4-yl)methanone (compound 7)

The same procedure as Example 3 was followed except that 5,7-Dichloro-6-nitro-1,2,3,4-tetrahydroisoquinoline was used to obtain the following structural compound. (Compound 7)

^1H NMR (300 MHz, CDCl ₃ ) δ ppm 8.26 (s, 1H), 7.52 (s, 1H), 5.61 (s, 1H), 4.71 (d, J = 30.9 Hz, 2H), 4.38 (d, J = 13.1 Hz, 2H), 3.87 (s, 2H), 3.80 (dd, J = 5.8, 4.0 Hz, 4H), 3.55 (t, J = 4.9 Hz, 4H), 2.96 (d, J = 16.3 Hz, 5H) ), 1.83 (s, 4H).

Example 10. (6,7-Dichloro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)(1-(6-morpholinopyrimidin-4-yl)piperidin-4-yl)methanone (compound 8)

The same procedure as in Example 3 was followed except that 6,7-Dichloro-1,2,3,4-tetrahydroisoquinoline was used, thereby obtaining the following structural compound. (Compound 8)

^1H NMR (300 MHz, CDCl ₃ ) δ ppm 8.25 (d, J = 0.9 Hz, 1H), 7.28 (s, 2H), 5.62 (s, 1H), 4.67 (d, J = 7.3 Hz, 2H), 4.38 (d, J = 13.2 Hz, 2H), 3.85 3.75 (m, 6H), 3.55 (dd, J = 5.7, 4.1 Hz, 4H), 3.03 2.81 (m, 5H), 1.82 (s, 4H).

Example 11. (1-(6-Morpholinopyrimidin-4-yl)piperidin-4-yl)(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 9)

The same procedure as in Example 3 was followed, except that 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 9)

^1H NMR (300 MHz, CDCl ₃ ) δ ppm 8.24 (d, J = 0.9 Hz, 1H), 7.44 (d, J = 11.9 Hz, 2H), 7.28 (s, 1H), 5.60 (s, 1H), 4.77 (d, J = 6.8 Hz, 2H), 4.37 (d, J = 13.3 Hz, 2H), 3.85 (d, J = 6.0 Hz, 1H), 3.81 3.75 (m, 5H), 3.56 3.50 (m, 4H) ), 3.04 2.84 (m, 5H), 1.83 (s, 4H).

Example 12. (1-(6-Morpholinopyrimidin-4-yl)piperidin-4-yl)(7-nitro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 10)

The same procedure as in Example 3 was followed except that 7-Nitro-1,2,3,4-tetrahydroisoquinoline was used, thereby obtaining the following structural compound. (Compound 10)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.26 (s, 1H), 8.07 (s, 2H), 7.36 (s, 1H), 5.63 (s, 1H), 4.85 (s, 2H), 4.40 (d, J = 12.9 Hz, 2H), 3.90 3.78 (m, 6H), 3.56 (d, J = 4.8 Hz, 4H), 3.03 (d, J = 17.4 Hz, 4H), 2.87 (s, 1H), 1.85 (s) , 4H).

Example 13. (5-Chloro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)(1-(6-morpholinopyrimidin-4-yl)piperidin-4-yl)methanone (compound 11)

The same procedure as Example 3 was followed except that 5-Chloro-1,2,3,4-tetrahydroisoquinoline was used, thereby obtaining the following structural compound. (Compound 11)

^1H NMR (300 MHz, CDCl ₃ ) δ 8.27 (s, 1H), 7.18 (t, J = 7.9 Hz, 1H), 7.10 (s, 1H), 5.63 (s, 1H), 4.74 (d, J = 15.2 Hz, 2H), 4.41 (d, J = 12.8 Hz, 2H), 3.80 (t, J = 5.0 Hz, 6H), 3.56 (t, J = 4.8 Hz, 4H), 2.95 (d, J = 33.0 Hz) , 5H), 1.85 (s, 4H).

Example 14. (1-Methyl-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)(1-(6-morpholinopyrimidin-4-yl)piperidin-4-yl)methanone (compound 12)

The same procedure as in Example 3 was followed except that 1-Methyl-1,2,3,4-tetrahydroisoquinoline was used, thereby obtaining the following structural compound. (Compound 12)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.24 (s, 1H), 7.23 - 7.12 (m, 4H), 5.65 (d, J = 7.4 Hz, 1H), 5.60 (d, J = 7.7 Hz, 1H) , 5.10 - 4.66 (m, 1H), 4.36 (dd, J = 31.5, 13.5 Hz, 2H), 3.95 (d, J = 13.5 Hz, 1H), 3.78 (s, 4H), 3.53 (s, 4H), 3.14 - 2.74 (m, 7H), 1.90 - 1.67 (m, 5H).

Example 15. 4-chloro-6-(1 H -Production of pyrrol-1-yl)pyrimidine

4,6-dichloropyrimidine (3.0 g, 20.00 mmol) was dissolved in THF (70 mL), and NaH (1.4 g, 60 mmol) was added at 0°C. Pyrrole (1.4 mL, 20 mmol) was slowly added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, water (100 mL) was added to the mixture, and ethyl acetate (100 mL) was used to extract twice. The organic extract was washed with brine (50 mL). The washed organic extract was dried over magnesium sulfate (MgSO4) and filtered. The filtrate was concentrated under reduced pressure, and 2.7 g (75%) of the title compound was obtained as a solid using column chromatography (E.A.:Hex=1:10).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 8.82 (d, J = 1.0 Hz, 1H), 8.05 (d, J = 1.1 Hz, 1H), 7.79 - 7.77 (m, 2H), 6.39 - 6.38 (m, 2H).

Example 16. 1-(6-(1 H Preparation of -pyrrol-1-yl)pyrimidin-4-yl)piperidine-4-carboxylic acid

4-chloro-6-(1H-pyrrol-1-yl)pyrimidine (5.8 g, 45.0 mmol), piperidine-4-carboxylic acid (11.60 g, 90.0 mmol), and K ₂ CO ₃ (15.5 g, 112.5 mmol) obtained in the above Example 15 were dissolved in dimethylformamide (60 mL) and stirred at 110°C for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, water (100 mL) was added, and the mixture was acidified (pH 4) with 1 N HCl. The acidified mixture was extracted twice using ethyl acetate (100 mL). The organic extract was washed with brine (50 mL). The washed organic extract was dried over magnesium sulfate (MgSO ₄ ) and then filtered. The filtrate was concentrated under reduced pressure, and column chromatography (EA:Hex=1:5) was used to obtain the title compound as a solid, 2.7 g (47%).

^1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 8.37 (s, 1H), 7.75 (t, J = 2.3 Hz, 2H), 6.95 (s, 1H), 6.29 (t, J = 2.3 Hz, 2H) ), 4.38 (dd, J = 10.8, 6.8 Hz, 2H), 3.14 - 3.06 (m, 2H), 2.59 (ddd, J = 11.0, 6.9, 4.0 Hz, 1H), 1.90 (dd, J = 13.4, 3.9 Hz, 2H), 1.52 (tt, J = 11.1, 5.7 Hz, 2H)

Example 17. (1-(6-(1 H -pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(6,7-dichloro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 13)

In Example 16, 1-(6-(1H-pyrrol-1-yl)pyrimidin-4-yl)piperidine-4-carboxylic acid (100 mg, 0.37 mmol), 6,7-dichloro-1,2,3,4-tetrahydroisoquinoline (90 mg, 0.44 mmol), HBTU (212 mg, 0.56 mmol), and triethylamine (Et ₃ N, 75 mg, 0.74 mmol) obtained were dissolved in dichloromethane (3 mL), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, water (10 mL) was added to the mixture, and extraction was performed twice using dichloromethane (10 mL). The organic extract was dried over magnesium sulfate (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the title compound was obtained as a solid (81 mg (50%)) using column chromatography (EA:Hex=1:3). (Compound 13)

^1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.48 (s, 1H), 7.51 (s, 2H), 7.29 (s, 2H), 6.41 (s, 1H), 6.37 (t, J = 2.3 Hz, 2H ), 4.69 (d, J = 10.4 Hz, 2H), 4.48 (d, J = 13.4 Hz, 2H), 3.85 (s, 1H), 3.78 (t, J = 5.8 Hz, 1H), 3.13 (ddd, J = 14.0, 10.4, 4.2 Hz, 2H), 2.91 (dd, J = 9.5, 4.5 Hz, 2H), 2.84 (s, 1H), 1.95 - 1.86 (m, 4H).

Example 18. (1-(6-(1 H -pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(6-fluoro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 14)

The same procedure as Example 17 was followed, except that 6-Fluoro-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 14)

^1H NMR (300 MHz, CDCl ₃ ) δ ppm 8.48 (s, 1H), 7.51 (t, J = 2.3 Hz, 2H), 7.14 (t, J = 7.0 Hz, 1H), 6.93 (d, J = 8.6) Hz, 2H), 6.41 (s, 1H), 6.36 (t, J = 2.3 Hz, 2H), 4.71 (d, J = 6.3 Hz, 2H), 4.49 (s, 2H), 3.87 - 3.76 (m, 2H) ), 3.17 - 3.09 (m, 2H), 2.99 - 2.90 (m, 3H), 1.91 (d, J = 5.9 Hz, 4H).

Example 19. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(5-chloro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 15)

The same procedure as Example 17 was followed except that 5-Chloro-1,2,3,4-tetrahydroisoquinoline was used, thereby obtaining the following structural compound. (Compound 15)

¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 8.45 (d, J = 3.2 Hz, 1H), 7.49 (t, J = 2.4 Hz, 2H), 7.32 - 7.26 (m, 1H), 7.17 (q, J = 7.8 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 6.39 (s, 1H), 6.34 (t, J = 2.3 Hz, 2H), 4.73 (d, J = 24.1 Hz, 2H), 4.47 (d, J = 15.1 Hz, 2H), 3.91 - 3.77 (m, 2H), 3.11 (ddd, J = 13.9, 10.6, 4.2 Hz, 2H), 2.99 (t, J = 6.0 Hz, 1H), 2.90 (q, J = 7.7, 6.3 Hz, 2H), 1.88 (dt, J = 10.9, 5.3 Hz, 4H).

Example 20. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(5,7-dichloro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 16)

The same procedure as Example 17 was followed except that 5,7-Dichloro-1,2,3,4-tetrahydroisoquinoline was used, thereby obtaining the following structural compound. (Compound 16)

^1H NMR (400 MHz, CDCl ₃ ) δ ppm 8.45 (s, 1H), 7.48 (t, J = 2.3 Hz, 2H), 7.30 (d, J = 12.3 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.38 (s, 1H), 6.34 (t, J = 2.3 Hz, 2H), 4.69 (d, J = 19.8 Hz, 2H), 4.46 (d, J = 13.3 Hz, 2H), 3.83 ( dt, J = 25.3, 6.0 Hz, 2H), 3.10 (ddd, J = 14.0, 10.4, 4.4 Hz, 2H), 2.96 - 2.82 (m, 3H), 1.87 (dt, J = 13.0, 6.2 Hz, 4H).

Example 21. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 17)

The same procedure as Example 17 was followed, except that 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 17)

^1H NMR (300 MHz, CDCl ₃ ) δ ppm 8.45 (d, J = 0.9 Hz, 1H), 7.48 (t, J = 2.3 Hz, 2H), 7.44 (d, J = 12.0 Hz, 2H), 7.30 ( d, J = 6.4 Hz, 1H), 6.39 (s, 1H), 6.34 (t, J = 2.3 Hz, 2H), 4.78 (d, J = 5.9 Hz, 2H), 4.46 (d, J = 13.4 Hz, 2H), 3.83 (dt, J = 19.0, 5.9 Hz, 2H), 3.17 - 3.05 (m, 2H), 3.00 (t, J = 6.0 Hz, 1H), 2.92 (s, 1H), 1.88 (d, J = 6.2 Hz, 4H).

Example 22. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(6-fluoro-4,4-dimethyl-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 18)

The same procedure as Example 17 was followed, except that 6-Fluoro-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 18)

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 8.47 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 2.3 Hz, 2H), 7.13 - 6.99 (m, 2H), 6.92 (p, J = 4.9 Hz, 1H), 6.40 (d, J = 2.8 Hz, 1H), 6.35 (t, J = 2.3 Hz, 2H), 4.74 (d, J = 3.2 Hz, 2H), 4.56 - 4.40 (m, 2H) ), 3.58 (d, J = 35.5 Hz, 2H), 3.11 (t, J = 12.4 Hz, 2H), 2.97 (q, J = 5.1, 4.5 Hz, 1H), 1.89 (d, J = 4.3 Hz, 4H), 1.35 (s, 3H), 1.27 (s, 3H).

Example 23. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(6,7-dichloro-4,4-dimethyl-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 19)

The same procedure as Example 17 was followed, except that 6,7-Dichloro-4,4-dimethyl-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 19)

^1H NMR (300 MHz, CDCl ₃ ) δ ppm 8.46 (s, 1H), 7.49 (s, 2H), 7.40 (d, J = 10.6 Hz, 1H), 7.21 (d, J = 1.0 Hz, 1H), 6.39 (s, 1H), 6.34 (t, J = 2.3 Hz, 2H), 4.71 (s, 2H), 4.46 (s, 2H), 3.55 (d, J = 36.0 Hz, 2H), 3.09 (t, J) = 11.6 Hz, 2H), 2.93 (dt, J = 10.0, 5.2 Hz, 1H), 1.89 (d, J = 15.2 Hz, 4H), 1.34 (s, 3H), 1.26 (d, J = 2.1 Hz, 3H).

Example 24. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(6,7-dichloro-1,1-dimethyl-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 20)

The same procedure as Example 17 was followed, except that 7,8-Dichloro-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 20)

^1H NMR (300 MHz, CDCl ₃ ) δ ppm 8.46 (s, 1H), 7.49 (s, 2H), 7.33 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 8.3 Hz, 1H), 6.39 (s, 1H), 6.34 (t, J = 2.3 Hz, 2H), 4.73 (d, J = 11.0 Hz, 2H), 4.46 (t, J = 16.5 Hz, 2H), 3.55 (d, J = 29.8 Hz, 2H), 3.10 (s, 2H), 2.97 (s, 1H), 1.89 (d, J = 15.4 Hz, 4H), 1.52 (d, J = 24.9 Hz, 6H).

Example 25. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(7-bromo-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 21)

The same procedure as Example 17 was followed, except that 7-Bromo-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 21)

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 1.83-1.90 (m, 4H), 2.79-2.92 (m, 3H), 3.05-3.15 (m, 2H), 3.77 (t, J=5.8Hz, 1H), 3.83(t, J=6.0Hz, 1H), 4.46(d, J=8.0Hz, 2H), 4.70(d, J=9.0Hz, 2H), 6.34(t, J=2.3Hz, 2H), 6.39( s, 1H), 7.05(t, J=6.0Hz, 1H), 7.31-7.36(m, 2H), 7.49(t, J=2.3Hz, 2H), 8.46(s, 1H).

Example 26. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(6-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 22)

The same procedure as Example 17 was followed, except that 6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 22)

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 1.78-1.96 (m, 4H), 2.86-2.98 (m, 2H), 3.03-3.17 (m, 3H), 3.79-3.89 (m, 2H), 4.40-4.50 (m, 2H), 4.86(s, 1H), 4.97(s, 1H), 6.34-6.40(m, 3H), 7.30-7.36(m, 2H), 7.49(d, J=2.0Hz, 2H), 7.56(d, J=6.5Hz, 1H), 8.45(s, 1H).

Example 27. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(7-nitro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 23)

The same procedure as Example 17 was followed, except that 7-Nitro-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 23)

¹ H NMR (300MHz, CDCl ₃ ) δ ppm 1.84-2.00 (m, 4H), 2.88-3.20 (m, 5H), 3.70-3.98 (m, 2H), 4.45 (d, J=7.1Hz, 2H), 4.84(s, 2H), 6.35(s, 2H), 6.39(s, 1H), 7.31-7.37(m, 1H), 7.49(s, 2H), 8.07-8.10(m, 2H), 8.46(s, 1H).

Example 28. Methyl (R)-2-(1-(6-(1 H Preparation of -pyrrol-1-yl)pyrimidin-4-yl)piperidine-4-carbonyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Compound 24)

The same procedure as Example 17 was followed, except that methyl (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate was used, to obtain the following structural compound. (Compound 24)

¹ H NMR (300MHz, CDCl ₃ ) δ ppm 1.82-2.06(m, 5H) 3.01-3.24(m, 5H) 3.63(s, 3H) 4.40-4.52(m,, 3H) 1.66(s, 1H) 5.43- 5.46(m, 1H) 634-6.39(m, 3H) 7.17-7.49(m, 4H) 7.49(t, J=2.01, 2H) 8.46(s, 1H).

Example 29. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 25)

The same procedure as Example 17 was followed except that 1,2,3,4-Tetrahydroisoquinoline was used, thereby obtaining the following structural compound. (Compound 25)

^1H NMR (300Hz, CDCl ₃ ) δ ppm 1.83-1.93 (m, 4H), 2.84-2.97 (m, 3H), 3.05-3.14 (m, 2H), 3.77 (t, J = 5.8Hz, 1H), 3.84 (t, J = 5.9Hz, 1H), 4.44-4.48 (m, 2H), 4.74 (d, J = 8.5Hz, 2H), 6.33 (t, J = 2.2Hz, 2H), 6.38 (s, 1H) ), 7.17-7.24 (m, 4H), 7.48 (s, 2H), 8.45 (s, 1H).

Example 30. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(5-amino-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 26)

The same procedure as Example 17 was followed except that 2,3,4-Tetrahydroisoquinolin-5-amine was used, thereby obtaining the following structural compound. (Compound 26)

¹ H NMR (DMSO) δ ppm 1.52-1.57(m, 4H), 2.52-2.61(m, 3H), 3.05-3.10(m, 2H), 4.50-4.66(m, 2H), 4.9(s, 2H) 6.29(s, 2H), 6.30(m, 2H), 7.75(s, 2H), 9.37(s, 1H).

Example 31. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(6-chloro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 27)

The same procedure as Example 17 was followed, except that 6-Chloro-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following chemical formula compound. (Compound 27)

¹ H NMR (300MHz, CDCl ₃ ) δ ppm 1.83-1.879m, 4H) 2.82-2.94(m, 3H) 3.06-3.15(m, 2H) 3.4-3.85(m, 2H) 4.41-4.50(m, 2H) 4.69(d, J=7.14, 2H) 6.34(t, J=2.2, 2H) 6.39(s, 1H) 7.07-7.10(m, 1H) 7317-7.21(m, 2H) 7.48-7.49(m, 2H) 8.45(s, 1H).

Example 32. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(7-chloro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 28)

The same procedure as Example 17 was followed except that 7-Chloro-1,2,3,4-tetrahydroisoquinoline was used, thereby obtaining the following chemical formula compound. (Compound 28)

¹ H NMR (300MHz, CDCl ₃ ) δ ppm 1.88-1.89 (m, 4H), 2.83-2.85 (m, 1H), 2.91 (d, J=10.7Hz, 2H), 3.75-3.83 (m, 2H), 4.43-4.48(m, 2H), 4.69(d, J=8.8Hz, 2H), 6.34(s, 2H), 6.39(s, 1H), 7.10-7.18(m, 3H), 7.49(s, 2H) , 8.46(s, 1H).

Example 33. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(7-fluoro-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 29)

The same procedure as Example 17 was followed except that 7-Fluoro-1,2,3,4-tetrahydroisoquinoline was used, thereby obtaining the following structural compound. (Compound 29)

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 1.88-1.95 (m, 4H), 2.81-2.95 (m, 3H), 3.06-3.16 (m, 2H), 3.75-3.86 (m, 2H), 4.46 (d) , J=8.0Hz, 2H), 4.70(d, J=8.9Hz, 2H), 6.35(s, 2H), 6.39(s, 1H), 6.85-6.96(m, 2H), 7.10-7.41(m, 1H), 7.49(s, 2H), 8.46(s, 1H).

Example 34. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(3-methyl-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 30)

The same procedure as Example 17 was followed except that 1-Methyl-1,2,3,4-tetrahydroisoquinoline was used, thereby obtaining the following structural compound. (Compound 30)

¹ H NMR (300MHz, CDCl ₃ ) δ ppm 1.44(d, J=6.8Hz, 2.2H), 1.75-2.08(m, 4.9H), 2.73-3.01(m, 3.6H), 3.01-3.18(m, 2.9H), 3.52-3.64(m, 0.9H), 3.93-4.01(m, 0.9H), 4.46(t, J=13.0Hz, 2.4H), 4.07-4.76(m, 0.6H), 5.08-5.13 (m, 0.6H), 5.67(q, J=3.7Hz, 0.9H), 6.34(s, 2H), 6.42(s, 1H), 7.11-7.23(m, 4H), 7.49(s, 2H), 8.46(s, 1H).

Example 35. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(5-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 31)

The same procedure as Example 17 was followed, except that 5-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 31)

¹ H NMR (300 MHz, CDCl ₃ ) δ ppm 1.84-1.93 (m, 4H), 2.90-3.15 (m, 5H), 3.79-3.87 (m, 2H), 4.43-4.50 (m, 2H), 4.78 (d) , J=7.2Hz, 2H), 6.35(t, J=2.1Hz, 2H), 6.39(s, 1H), 7.26-7.29(m, 2H), 7.43-7,49(m, 3H), 8.46( s, 1H).

Example 36. (1-(6-(1 H -Pyrrol-1-yl)pyrimidin-4-yl)piperidin-4-yl)(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H Preparation of )-yl)methanone (compound 32)

The same procedure as Example 17 was followed, except that 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline was used, to obtain the following structural compound. (Compound 32)

^1H NMR (300Hz, CDCl ₃ ) δ ppm 1.87-1.92 (m, 4H), 2.77-2.91 (m, 3H), 3.06-3.15 (m, 2H), 3.76 (t, J = 5.7Hz, 1H), 3.81-3.86 (m, 7H), 4.42-4.47 (m, 2H), 4.65 (d, J = 6.1Hz, 2H), 6.33 (t, J = 2.2Hz, 2H), 6.38 (s, 1H), 6.62 -6.63 (m, 2H), 7.48 (t, J = 2.1Hz, 2H), 8.45 (s, 1H).

Example 37. N-(2-(1-(6-(1 H - Manufacture of pyrrol-1-yl)pyrimidin-4-yl)piperidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)acetamide (Compound 33)

Compound 26 (80 mg, 0.2 mmol) obtained in the above Example 30 and acetyl chloride (15.7 mg, 0.2 mmol) were dissolved in M.C. (1.0 mL) and stirred at room temperature for 12 hours. After completion of the reaction, water (10 mL) was added to the mixture and extracted twice using dichloromethane (10 mL). The organic extract was dried over magnesium sulfate (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and 46 mg (51%) of the following structural compound of the above chemical formula was obtained in the form of a solid using column chromatography (1% M.C.). (Compound 33)

¹ H NMR (CDCl ₃ ) δ ppm 1.61-1.75(m, 1H)1.81-1.9.(m, 4H)2.21(s, 3H)2.69-2.71(m, 1H)2.81-2.97(m, 2H)3.05- 3.18(m, 2H)3.75-3.92(m, 2H)4.41-4.47(m, 2H)4.75(m, 2H)6.35(d, J=12Hz, 3H7.00-7.10(m, 2H)7.22-7.24( m, 1H)77.48(s, 2H) 8.45(s, 1H).

Example 38. 1-(2-(1-(6-(1 H - Preparation of pyrrol-1-yl)pyrimidin-4-yl)piperidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)-3-phenylurea (compound 34)

The same procedure as in Example 37 was followed except that phenylcarbamic chloride was used, thereby obtaining the following structural compound. (Compound 34)

¹ H NMR (CDCl ₃ ) δ ppm 1.87-1.88(s, 4H)2.61-2.78(m, 3H)2.85-3.02(m, 3H)3.58(s, 1H)3.77(s, 1H)4.38-4.45(m , 2H)4.63-4.69(m, 2H)6.27(s, 1H)6.32 (s, 2H)6.82-6.97(m, 2H) 6.98-7.13(m, 2H)7.20-7.31(m, 2H)7.69(d , J=7.8Hz, 1H)7.42-7.50(m, 2H) 8.28(s, 1H)8.41(d,J=5.5Hz, 1H).

Example 39. N-(2-(1-(6-(1 H - Manufacture of pyrrol-1-yl)pyrimidin-4-yl)piperidine-4-carbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide (Compound 35)

The same procedure as Example 37 was followed except that benzoyl chloride was used, thereby obtaining the following structural compound. (Compound 35)

¹ H NMR (CDCl ₃ ) δ ppm 1.87-1.88(m, 4H) 2.61-2.70(m,3H) 2.90-3.02(m,3H)3.58(s, 1H)3.77(s, 1H)4.38-4.45(m ,2H)4.63-4.69(m, 2H)6.27-6.32(m, 3H)6.82-6.97(m, 2H) 6.98-7.13(m, 4H)7.18-7.31(m,2H) 7.7.44-7.50(m , 2H)8.28(s, 1H)8.41(m, 1H).

^{The 1H} NMR analysis confirmation data of Examples 40 to 77 below are summarized in Table 1 below.

[Experimental Example 1]

The efficacy of the compound obtained in the above example against tuberculosis bacteria was confirmed as follows, and the results are shown in Table 2 below.

(1-1) Efficacy against tuberculosis bacteria

In order to evaluate the efficacy of the compound of the present invention against tuberculosis bacteria, the following experiment was conducted using the tuberculosis minimum inhibitory concentration (MIC) measurement method.

In the examples of the present invention, the obtained compounds were serially diluted 2-fold using Middlebrook 7H9 liquid medium (obtained from Difco, USA), and 50 μL was dispensed into 96-well microplates. The frozen stock of Mycobacterium tuberculosis H37Rv, a standard strain of tuberculosis, was inoculated into Middlebrook 7H9 liquid medium and cultured for 5 days. When the absorbance at a wavelength of 600 nm was 0.5, the solution was diluted and 50 μl was inoculated into the drug dilution plate so that the final bacterial count was 2-5 X 10 ⁵ colonies/ml. After culturing the test plate at 37°C for 7 days, 10 μl of Alamar Blue indicator was added to each well. After 24 hours, the color change of each well was observed, and the lowest concentration that remained blue was determined as the minimum inhibitory concentration. The results of the inhibitory activity (MIC) of the compound of the present invention against Mycobacterium tuberculosis are shown in Table 2 below.

As shown in Table 2 above, it can be confirmed that the compound, which is a tetrahydroisoquinoline derivative containing pyrimidine of the present invention, exhibits an excellent effect against tuberculosis bacteria. Specifically, the compound in which R ₁ in the chemical formula 1 of the present invention is substituted with morpholine or pyrrole exhibits excellent activity.

(1-2) Efficacy against drug-resistant tuberculosis bacteria

As a result of comparing the activity of the compound of the present invention on resistant strains, it exhibited excellent effects on resistant strains, as shown in Table 2 below. The experimental method for measuring the activity of drug-resistant tuberculosis bacteria was as follows.

- Fungal culture

Drug-resistant tuberculosis strains were cultured for 3-4 weeks in culture medium containing M7H9 broth, 10% AS, 0.05% tyloxapol, and 10 mM sodium butyrate.

- Experimental method

① Dispense 100 μl of culture medium into each well of a 96-well plate. All experiments are performed in triplicate.

② Dispense 100 ul of the compound into each top well (2B, 2C, 2D or 2E, 2F, 2G) according to each concentration, and serially dilute up to 8 steps using a 2-fold dilution.

③ After measuring the OD value of the prepared drug-resistant bacteria (Spectrophotometer OD600nm), dilute to OD 0.1/ml and dispense 100ul into each well.

④ Wrap the prepared plate well with aluminum foil and incubate in an incubator at 5% CO2 and 37℃ for 2 weeks.

⑤ Add 20 μl of 0.025% resazurin sodium salt (R7017, SIGMA, 2.5 mg + DW10 ml) to each well and culture for 2 more days.

⑥ After visually confirming the color development, measure the OD value using a spectrophotometer.

The results were evaluated by indicating growth of Mtb as pink and no growth of Mtb as blue, and an example of measuring the activity of Isoniazid against one drug-resistant strain is shown in Figure 1. In addition, the results of the inhibitory activity of the compound of the present invention against Mycobacterium tuberculosis-resistant strains are summarized in Table 3 below.

Therefore, the tetrahydroisoquinoline derivative containing pyrimidine of the present invention can be very usefully utilized in the development of an anti-tuberculosis agent.

Claims (7)

A tetrahydroisoquinoline derivative comprising a pyrimidine represented by the following chemical formula 2 or 3, or a pharmaceutically acceptable salt thereof:
[Chemical formula 2]

[Chemical Formula 3]

In the above chemical formulas 2 and 3,
R ₂ is hydrogen, halogen, amino, (C ₁ -C ₇ )alkyl or (C ₁ -C ₇ )alkyloxy substituent;
R ₃ is independently hydrogen, (C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkoxycarbonyl or di(C ₁ -C ₇ )alkylaminocarbonyl substituent;
R ₄ is independently hydrogen or (C ₁ -C ₇ )alkyl;
R ₅ is independently a halogen or a halo(C ₁ -C ₇ )alkyl substituent;
R ₆ is independently hydrogen, halogen, nitro, amino, aldehyde, carboxylic acid, (C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkoxy, hydroxy(C ₁ -C ₇ )alkyl, (C ₁ -C ₇ )alkylaminocarbonyl, or a di(C ₁ -C ₇ )alkylaminocarbonyl substituent;
Ak is (C ₁ -C ₇ )alkyl;
m is an integer from 1 to 4;
n is an integer from 0 to 2; delete delete delete A pharmaceutical composition for preventing or treating tuberculosis, characterized in that it contains as an active ingredient at least one selected from the tetrahydroisoquinoline derivatives containing pyrimidine according to the first clause or pharmaceutically acceptable salts thereof. In paragraph 5,
A pharmaceutical composition for preventing or treating tuberculosis, characterized in that the composition contains 0.001 to 1 wt% of an effective ingredient. In paragraph 5,
A pharmaceutical composition wherein the composition further comprises a pharmaceutically acceptable carrier, diluent or excipient.